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Friday, June 1, 2018

Promise of regenerating tissues and organs from inside the body


Regenerative medicine holds tremendous promise for many ailments, from curing diabetes with pancreatic cell transplants to growing new organs for transplant. But because these approaches generate tissue ex vivo, or outside the body, scientists developing them all face the same conundrum: How can they connect these externally developed tissues to the bloodstream and the rest of the body so they can thrive?
Scientists in Wendell Lim’s lab at UC San Francisco hope that a synthetic signaling molecule, dubbed synNotch, will allow scientists to create tissues and organs within the body, with ready-made connections. They used synNotch to program groups of cells to differentiate into different types of structures, mimicking how cells naturally “talk” to each other and decide how to organize themselves into tissues, according to a statement. Specifically, they programmed cells to respond to signals coming from adjacent cells by making “sticky” molecules called cadherins and fluorescent marker proteins.
They made a series of increasingly more complicated structures, starting with a two-layered sphere. A group of colorless cells expressing synNotch were programmed to detect a signal protein expressed by a second group of blue cells. When combined, the blue cells activated the clear cells’ synNotch, prompting them to produce the velcro-like cadherins and a green marker protein. This caused the colorless cells to clump together and turn green, forming the core of the sphere, surrounded by an outer layer of blue cells.
While the structures the team built were relatively simple, “these minimal intercellular programs were sufficient to yield assemblies with hallmarks of natural developmental systems: robust self-organization into multidomain structures, well-choreographed sequential assembly, cell type divergence, symmetry breaking and the capacity for regeneration upon injury,” they wrote in their study, which appears in Science. Lim thinks that combining multiple layers of synNotch signaling will pave the way for the generation of “ever more complex” tissues.
“People talk about 3D-printing organs, but that is really quite different from how biology builds tissues. Imagine if you had to build a human by meticulously placing every cell just where it needs to be and gluing it in place,” said Lim, a Howard Hughes Medical Institute investigator and member of the UCSF Helen Diller Family Comprehensive Cancer Center, in the statement. “It’s equally hard to imagine how you would print a complete organ, then make sure it was hooked up properly to the bloodstream and the rest of the body. The beauty of self-organizing systems is that they are autonomous and compactly encoded. You put in one or a few cells, and they grow and organize, taking care of the microscopic details themselves.”
In a similar tack, researchers in the U.S. and Japan developed a new cell culture method to combat a problem with pancreatic islets—the tendency to lose their blood vessels when they are being prepared for transplant. The method, called self-condensation cell culture, allowed the scientists to grow new pancreatic islets complete with endothelial cells, which improved post-transplant engraftment.
SynNotch was first developed in Lim’s lab by co-authors Kole Roybal and Leonardo Morsut. At the time, they used it to tweak T cells, improving their ability to recognize cancer cells and destroy them. The technology has the potential to make engineered T-cell treatments more specific and therefore applicable in solid tumors. It could also be used to suppress the immune response, which could be useful in treating autoimmune disease, the scientists said at the time.

GSK collaborates on AI-driven drug design with Cloud Pharmaceuticals


GlaxoSmithKline (GSK) is set to apply artificial intelligence (AI) technology to improve its drug discovery efforts through a collaboration with Cloud Pharmaceuticals.
Its deal with the US-based AI-driven drug design and development company will see Cloud design novel small-molecule agents to GSK-specified targets.
Ed Addison, CEO of Cloud Pharmaceuticals, said: “Application of Cloud Pharmaceuticals technology has been proven to dramatically shorten the time from target validation to lead molecule.
“We believe this agreement validates the strength of this process and reinforces the value we can offer accelerate the discovery of novel, high-quality drug candidates.”
Set up in 2009, Cloud aims to use its technology to accelerate the drug discovery and design process by using a proprietary AI-driven process to deliver novel molecules tailored to a drug target’s characteristics.
Don Van Dyke, COO of Cloud, said: “It is estimated that the traditional discovery process to arrive at a clinical candidate molecule takes greater than five years. Cloud has consistently been able to reduce that to a matter of a few months.”
The collaboration marks Cloud’s first big pharma deal, but for GSK it adds to the $33 million deal it signed with Scotland’s ExScientia last year to apply that firm’s AI technology to speed up its drug discovery efforts.
It is, however, GSK’s first major AI move since appointing Karenann Terrell last July to the newly-created post of chief digital and technology officer.
Commenting then on Terrell’s appointment GSK chief executive Emma Walmsley said Terrell would be given the scope to “think radically about how we can exploit the latest opportunities and ultimately improve our business performance”.
But GSK isn’t the only company looking to buck the continuing downward trend in conventional pharma R&D productivity by harnessing new technology.
Two of the sector’s latest deals have seen Pfizer partner with US-based AI firm XtalPi to develop molecular modelling software for drug-like small molecules and Mitsubishi Tanabe Pharma tie up with Hitachi to apply AI to improve the efficacy of its drug development efforts.

FDA approves UCB’s Cimzia in plaque psoriasis


The US FDA has approved a label extension for UCB’s Cimzia (certolizumab pegol) for adults with moderate-to-severe plaque psoriasis, marking the company’s entry into immuno-dermatology, an area with significant unmet need.
Cimzia is indicated for the treatment of adults with moderate-to-severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy. The approval makes Cimzia the first Fc-free, PEGylated anti-TNF treatment option for this indication.
Lead investigator Alice Gottlieb, Professor of Dermatology at New York Medical College, said that the phase 3 clinical development programme for Cimzia in plaque psoriasis demonstrated statistically significant improvements in efficacy endpoints at week 16, with a clinically meaningful response maintained up to week 48.
“This compelling body of evidence is especially significant for a disease like psoriasis, which often has significant emotional and social burdens in addition to the more widely-recognised physical symptoms,” she explained. “The two dose regimens of Cimzia also allow for patient-tailored treatment.”
Emmanuel Caeymaex, head of Immunology and executive vice president, Immunology Patient Value Unit, at UCB, said, “The approval of Cimzia for psoriasis and the recent Cimzia label update regarding pregnancy and breastfeeding in women with chronic inflammatory diseases are important treatment advances. UCB is committed to improving care for psoriasis patients and is also investigating bimekizumab, a therapy with significant potential for psoriasis patients.”
This FDA approval is based on data from a phase 3 clinical development programme, comprising CIMPASI-1, CIMPASI-2 and CIMPACT. The trials enrolled over 1,000 patients, nearly one third of whom had prior biologic exposure.
Each of the three studies included an assessment of the percentage of patients who achieved at least 75% and 90% or greater disease improvement from baseline, as measured by the Psoriasis Area and Severity Index (PASI 75 and PASI 90, respectively) compared to placebo.
The positive findings from the trials, and the new approval in psoriasis that they support, are significant because they build on four years of efficacy and safety data in psoriatic arthritis (PsA).
The recommended dose of Cimzia for adults with moderate-to-severe plaque psoriasis is 400 mg (given as two subcutaneous injections of 200 mg each) every other week. For some patients (with body weight ≤ 90 kg), Cimzia 400 mg (given as two subcutaneous injections of 200 mg each) initially and at weeks 2 and 4, followed by 200 mg every other week can be considered.
“Due to the unique nature of psoriasis, it is critical for dermatologists to have as many options as possible to find the right treatment for each patient,” said Michael Siegel, PhD, senior vice president of Research and Clinical Affairs, National Psoriasis Foundation.
Psoriasis is a common, chronic inflammatory disease primarily affecting the skin. Signs and symptoms vary but may include red patches of skin covered with silvery scales, dry, cracked skin that may bleed and thickened, pitted or ridged nails.
Psoriasis affects nearly 3% of the population, or approximately 125 million people worldwide. Those with more severely affected, psoriasis can have a major impact on their quality of life. As many as 42% of patients develop psoriatic arthritis, 33% develop metabolic syndrome, and approximately 46% are depressed because of their psoriasis.

TESARO: Ovarian cancer med added to Cancer Drugs Fund in UK

  • Inclusion in the Cancer Drugs Fund will give more women in England and Wales with recurrent, platinum-sensitive ovarian cancer access to ZEJULA via a managed access arrangement
  • ZEJULA was launched in the private market in the UK at the end of 2017
TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, today announced the National Institute for Health and Care Excellence (NICE) will make ZEJULA® (niraparib), the first PARP inhibitor shown to be effective in patients with a BRCA mutation as well as those without a BRCA mutation, available to women in England and Wales with recurrent platinum-sensitive ovarian cancer via the Cancer Drugs Fund (CDF)1.  NICE has recommended ZEJULA via the CDF for women with a BRCA mutation who have received two lines of chemotherapy and in women without a BRCAmutation who have received two or more lines of chemotherapy.
“At TESARO, we continue to globalize our mission and bring transformative therapies to patients. We are pleased that NICE will now provide more women with recurrent ovarian cancer in England and Wales access to ZEJULA through the CDF,” said Orlando Oliveira, Senior Vice President and General Manager, TESARO International. “Through close partnership with both NICE and NHS, TESARO can now offer ZEJULA as an option for second-line maintenance treatment, regardless of a patient’s BRCA status.”
The CDF is a source of funding for cancer drugs in England, providing patients access to promising new oncology treatments while NHS England and NICE analyze any additionally requested data to inform a final reimbursement decision on a new treatment or indication. Overall survival data for ZEJULA are not yet available, and as a result NICE has recommended ZEJULA for use within the CDF while further data are collected2. Interim funding is provided via the CDF, giving patients access to the treatment through a managed access arrangement.
“Recurrent ovarian cancer is an aggressive form of cancer where a key goal of treatment is to keep women in remission and off chemotherapy for as long as possible – allowing them the best chance for a good quality of life,” said Jonathan Ledermann, Professor of Medical Oncology at the University College London Cancer Institute. “ZEJULA offers the chance to delay this cancer from returning or progressing for months, and possibly years in some cases. It is a significant step forward. Crucially, this decision opens the door for many women who, until now, have not had the option of maintenance treatment with a PARP inhibitor.”

#ASCO18: Bluebird & Celgene CAR-T nears 1 year of survival in multiple myeloma


Bluebird Bio and Celgene have built upon their already impressive early-stage clinical responses in advanced multiple myeloma, now confirming that their bb2121 CAR-T therapy extended progression-free survival to just shy of one year in a new set of phase 1 data.
In 18 participants receiving larger infusions of 150 million CAR-T cells or more—engineered to target B-cell maturation antigen, or BCMA, a protein on the surface of certain myeloma cells—the dose-escalation study saw a median PFS of 11.8 months. Meanwhile, the 16 patients across the study who saw their disease go into remission demonstrated a median PFS of 17.7 months, according to the companies’ presentation Friday at the annual meeting of the American Society of Clinical Oncology in Chicago.
Additionally, the new data showed little difference in overall response rates between patients with low or high levels of BCMA expression at high doses, meaning that future patients will not need to be segmented or tested with a diagnostic—an important distinction to note as the two companies look to file bb2121 with the FDA before the end of 2019, Bluebird CEO Nick Leschly told FierceBiotech.
Last December, in a presentation at the American Society of Hematology’s annual meeting, the companies demonstrated an 86% overall response rate, with 56% of patients in remission nine months after a single dose.
Now, the study—which has been expanded from 21 to 43 patients—also showed no new safety signals, including severe or fatal cases of cytokine release syndrome or neurotoxicity. While 63% of patients had a CRS event, the companies described them as manageable.
“That safety profile is incredibly important,” Leschly said. “Not only because you want it for patients, but also if you want to consider using this treatment in earlier myeloma patients, which we certainly do.”
Currently, bb2121 is being tested in heavily-treated multiple myeloma patients whose disease had relapsed after becoming refractory to multiple standard therapies. Two deaths in the study had been reported at ASH, linked to cardiac arrest and myelodysplastic syndrome. Both patients had demonstrated complete responses at their last assessments.

This year, Bluebird and Celgene hope to begin pursuit of bb2121 in earlier indications, step-by-step, Leschly said—including a planned phase 3 trial in third-line multiple myeloma compared to a triplet regimen of daratumumab (Genmab and Janssen’s Darzalex) plus pomalidomide (Celgene’s Pomalyst) and dexamethasone, a corticosteroid.
After that, the companies plan to explore label expansions in second-line therapy, followed by exploration in newly diagnosed disease compared to stem cell transplants.
“We believe our profile of efficacy and safety is very conducive to starting to move earlier lines of treatment,” he said. “That’s ultimately where the game will be played.”

Enrollment in a pivotal phase 2 trial, KarMMa, is already underway, which will be used to support the expected 2019 filing in later lines of treatment. The study plans to examine overall response rate in 80 relapsed and refractory patients who have previously received three or more treatment regimens.
KarMMa’s design also dovetails nicely with the phase 1 results, Leschly described, with certain elements being baked into the protocol along the way, such as aims for the higher end of the dose range and no delineation based on BCMA expression.
“As you now have refined and more targeted doses, one could hope that this data would be as good, if not better, over time,” he said. “But that’s what we need to go show.”

FDA lifts partial hold on Bristol-Myers myeloma med study


Bristol-Myers Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) lifted a partial clinical hold placed on CA209-602 (CheckMate -602), a randomized, open-label Phase 3 study evaluating the addition of Opdivo (nivolumab) to pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. The decision follows consultation with the FDA and agreement on amendments to the study protocol.
Three trials evaluating Opdivo-based combinations in relapsed or refractory multiple myeloma were placed on partial clinical hold in September 2017 as an FDA precaution following risks identified in trials studying another anti–PD-1 agent, pembrolizumab, in patients with multiple myeloma. CheckMate -602 is the last of the three trials to have its partial clinical hold lifted following a similar FDA action announced in December 2017, when the agency lifted partial holds on CA209-039 (CheckMate -039) and CA204-142.

Own Agios For ‘The Next Several Years’: Piper


Agios Pharmaceuticals Inc AGIO 3.59%, a pharmaceutical company that focuses on the field cellular metabolism to treat cancer and rare genetic diseases, is a stock investors should “own for the next several years,” according to Piper Jaffray.

The Analyst

Piper Jaffray’s Tyler M. Van Buren initiated coverage of Agios Pharmaceuticals with an Overweight rating and $125 price target.

The Thesis

The bullish case for owning Agios’ stock is four-fold, Van Buren said in a note.
  • Agios and its partner Celgene CELG 0.46% received approval for its idhifa therapyand so far the launch has “gone well” and represents $200 million in potential U.S. sales. The company’s tibsovo therapy is similar to idhifa and is under review but should be approved by the end of 2018 and generate another $100 to $150 million in potential sales.
  • Idhifa and tibsovo have shown “encouraging data” in frontline AML, but Van Buren said the opportunities for the therapies will likely expand. Tibsovo, for example, is in a Phase 1 development cholangiocarcinoma and low-grade glioma.
  • Phase 2 data for the company’s AG-348 for the treatment pf Pyruvate Kinase Deficiency is favorable so far and indicates a durable 3.4 g/dL increase of hemoglobin in 50 percent of PKD patients.
  • Agios faces a “very large” potential opportunity with its AG-270 for MTAP-deleted tumors. The company is expected to show initial data by early 2019 the latest and could ultimately serve more than 100,000 patients with MTAP-deleted tumors.